title: Oncogenic activity of retinoic acid receptor γ is exhibited through activation of the Akt/NF-κB and Wnt/β-catenin pathways in cholangiocarcinoma.
abstract: Aberrant expression and function of retinoic acid receptor γ (RARγ) are often involved in the progression of several cancers. However, the role of RARγ in cholangiocarcinoma (CCA), chemoresistant bile duct carcinoma with a poor prognosis, remains unclear. In the present study, we found that RARγ was frequently overexpressed in human CCA specimens. Its overexpression was associated with poor differentiation, lymph node metastasis, high serum carbohydrate antigen 19-9 level, and poor prognosis of CCA. Downregulation of RARγ reduced CCA cell proliferation, migration, invasion, and colony formation ability in vitro and tumorigenic potential in nude mice. RARγ knockdown resulted in upregulation of cell cycle inhibitor P21, as well as downregulation of cyclin D1, proliferating cell nuclear antigen, and matrix metallopeptidase 9, in parallel with suppression of the Akt/NF-κB pathway. Furthermore, overexpression of RARγ contributed to the multidrug chemoresistance of CCA cells, at least in part due to upregulation of P glycoprotein via activation of the Wnt/β-catenin pathway. Molecular mechanism studies revealed that RARγ interacted with β-catenin and led to β-catenin nuclear translocation. Taken together, our results suggested that RARγ plays an important role in the proliferation, metastasis, and chemoresistance of CCA through simultaneous activation of the Akt/NF-κB and Wnt/β-catenin pathways, serving as a potential molecular target for CCA treatment.
authors.affiliation: Center Laboratory, First Affiliated Hospital of Xiamen University, Xiamen, People's Republic of China.
authors.forename: Gui-Li
authors.initials: GL
authors.lastname: Huang
authors.forename: Qi
authors.initials: Q
authors.lastname: Luo
authors.forename: Gang
authors.initials: G
authors.lastname: Rui
authors.forename: Wei
authors.initials: W
authors.lastname: Zhang
authors.forename: Qiu-Yan
authors.initials: QY
authors.lastname: Zhang
authors.forename: Qing-Xi
authors.initials: QX
authors.lastname: Chen
authors.forename: Dong-Yan
authors.initials: DY
authors.lastname: Shen
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics; D000818:Animals; D001650:Bile Duct Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D001652:Bile Ducts / Q000378:metabolism / Q000473:pathology; D002453:Cell Cycle; D049109:Cell Proliferation; D018281:Cholangiocarcinoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D015536:Down-Regulation; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D016328:NF-kappa B / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D018168:Receptors, Retinoic Acid / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation; D060449:Wnt Signaling Pathway; D051176:beta Catenin / Q000378:metabolism*; D000097768:Retinoic Acid Receptor gamma
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D016328:NF-kappa B; D051057:Proto-Oncogene Proteins c-akt; D018168:Receptors, Retinoic Acid; D051176:beta Catenin; D000097768:Retinoic Acid Receptor gamma